Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Food intake is significantly increased following administration of mu-selective opioid agonists into the ventral tegmental area (VTA) region acting through multiple local opioid receptor subtypes. Since GABA receptor agonists in the VTA region are capable of eliciting feeding, the present study investigated whether feeding elicited by the mu-selective opioid agonist [D-Ala(2), NMe(4), Gly-ol(5)]-enkephalin (DAMGO) in the VTA region was altered by pretreatment into the same site with equimolar doses of either GABA(A) (bicuculline) or GABA(B) (saclofen) antagonists, and further, whether pretreatment with either general opioid or selective GABA receptor antagonists decreased feeding elicited by GABA(A) (muscimol) or GABA(B) (baclofen) agonists in the VTA region. DAMGO-induced feeding in the VTA region was dose-dependently decreased following pretreatment with either GABA(A) or GABA(B) antagonists in the absence of significant alterations in food intake by the antagonists per se. However, the presence of short-lived seizures following bicuculline in the VTA region suggests that this ingestive effect was caused by nonspecific actions. In contrast, GABA(B) receptors are involved in the full expression of mu-opioid agonist-induced feeding in this region since saclofen failed to elicit either seizure activity or a conditioned taste aversion. Pretreatment with naltrexone in the VTA region reduced intake elicited by baclofen, but not muscimol. Finally, baclofen-induced feeding was significantly reduced by saclofen, but not bicuculline, pretreatment in the VTA region. Therefore, possible coregulation between GABA(B) and opioid receptors in the VTA region, as suggested by immunocytochemical evidence, is supported by these behavioral effects upon ingestion.
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PMID:Alterations in food intake elicited by GABA and opioid agonists and antagonists administered into the ventral tegmental area region of rats. 1217 94

Alpidem analogues containing a GABA (1-3) or glycine (4-6) moiety were synthesized and their interaction with the GABA/benzodiazepine receptor complex at central (CBR) and peripheral (PBR) level was evaluated. In particular, their ability to modulate the specific binding of [3H]-GABA to washed membrane preparations from the rat cerebral cortex, as well as their effects on human recombinant GABA(A) receptors in Xenopus laevis oocytes, were assessed. Results from these in vitro assays showed that the most active compounds were 1 and 4. Intraperitoneal administration of compound 1 at a dose of 150 mg/kg significantly antagonized pentylenetetrazole-induced seizures in rats and the protective effects were evident for 90 min. However, compound 4 failed to interact with strychnine-sensitive Gly-binding sites. Consistent with these binding results, intraperitoneal administration of compound 4 at 150 mg/kg showed no effect against convulsions induced by strychnine, except for a prolonged time of the latency of convulsions. The results obtained suggest that compound 1 possesses interesting anticonvulsant activity and deserves further investigation as a novel lipophilic GABA derivative.
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PMID:Alpidem analogues containing a GABA or glycine moiety as new anticonvulsant agents. 1265 34

In the present communication, the dynamic release of amino acid (AA) transmitters induced by valproate (VPA) in pentylenetetrazol (PTZ)-kindled freely moving rats hippocampus has been determined. The results showed that glutamate and aspartate release were significantly increased during the seizure/interical periods, and markedly decreased after the application of 200mg/kg valproate. In contrast, gamma-aminobutyric acid and taurine release were markedly decreased during interical period, and significantly increased during the seizure period. Glycine release was similar to the case of glutamate and aspartate release. The increase of either gamma-aminobutyric acid/taurine or glycine releases during the seizure period could be inhibited by the application of valproate likewise. The results indicate that: (a) the imbalance between excitatory and inhibitory neurotransmitters is really involved in epilepsy; (b) the modulation of valproate on the major amino acid neurotransmitters certainly plays one of important roles on antiepilepsy efficacy; (c) the pentylenetetrazol-kindled epileptogenesis model is a fit one for approaching the mechanisms of valproate modulating amino acid neurotransmitters.
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PMID:Dynamic release of amino acid transmitters induced by valproate in PTZ-kindled epileptic rat hippocampus. 1460 89

Interleukin-6-deficient (IL-6(-/-)) mice and their normal littermate (WT) were studied to evaluate their susceptibility to seizures induced by electroshock and audiogenic stimuli at different ages. No significant changes in maximal electroshock susceptibility were evidenced between the two strains, while audiogenic seizures (AGS) can be induced only in IL-6(-/-) mice. The effects of age and genetic condition on AGSs were evaluated. The behavioural and electrocortical changes during audiogenic stimulus were observed. In addition, the levels of neurotransmitter amino acids in five brain areas (of both strains) were measured at 60 days of age. Aspartate level significantly increased in the brain stem (BS) and hippocampus (HI), while it decreased in the diencephalon (DE) of IL-6(-/-) mice. Glutamate content significantly decreased in the cerebellum (CB), DE and HI. GABA levels significantly decreased in all the areas studied. Glycine significantly decreased in the BS, CB and DE, while taurine decreased only in the DE. The levels of glutamine significantly decreased in all the areas examined, except in the cortex (CX). The changes of neuroactive amino acid levels, particularly in the BS, might explain the characteristic of high propensity to AGS of IL-6(-/-) mice. The present data support the validity of IL-6(-/-) mice as a novel epileptic model for the study of the pathophysiology and pharmacology of epilepsy.
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PMID:Susceptibility to audiogenic seizure and neurotransmitter amino acid levels in different brain areas of IL-6-deficient mice. 1515 36

Alterations in the opioid system in the hippocampal formation and some of the possible functional consequences were investigated in adult male rats that were prenatally exposed to either saline or morphine (10 mg/kg twice daily on gestational days 11-18). In situ hybridization and Northern blots were used to measure proenkephalin and prodynorphin mRNA, and radioimmunoassays quantified proenkephalin- and prodynorphin-derived peptide levels in the dentate gyrus, CA3, and CA1 subfields of the hippocampal formation. Prenatal morphine exposure in male rats decreases proenkephalin and increases prodynorphin mRNA selectively in the granule cell layer of the dentate gyrus. Similarly, met-enkephalin peptide levels are decreased and dynorphin B peptide levels are increased in the dentate gyrus but not CA3 or CA1 of prenatally morphine-exposed males. In addition, there are decreases in dynorphin-derived peptides in the CA3 subfield. Receptor autoradiography revealed increases in the density of micro but not delta receptor labeling in discrete strata of specific hippocampal subfields in morphine-exposed males. Because alterations in the hippocampal opioid system suggest possible alterations in the excitability of the hippocampal formation, changes in opioid regulation of seizures were examined. Morphine exposure, however, does not alter the latency to onset or number of episodes of wet dog shakes or clonic seizures induced by infusion of 10 nmol [D-Ala2, MePhe4, Gly-ol5]enkephalin into the ventral hippocampal formation. Interestingly, a naloxone (5 mg/kg) injection 30 min before bicuculline administration reverses the increased latency to onset of clonic and tonic-clonic seizures in morphine-exposed males. Thus, the present study suggests that exposure of rats to morphine during early development alters the hippocampal opioid system, suggesting possible consequences for hippocampal-mediated functions.
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PMID:Field-specific changes in hippocampal opioid mRNA, peptides, and receptors due to prenatal morphine exposure in adult male rats. 1520 53

Fast oscillations at approximately 200 Hz, termed ripples, occur in the hippocampus and cortex of several species, including humans, and are thought to play a role in physiological (e.g., sensory information processing or memory consolidation) and pathological (e.g., seizures) processes. Blocking gamma-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition represents one of the most often used models of epileptiform discharge. Here we found that bath application of the GABA(A) receptor antagonist picrotoxin (50 microM) to mouse hippocampus-entorhinal cortex slices induced spontaneous epileptiform activity (duration 536.6 +/- 146.1 msec, mean +/- SD; interval of occurrence 14.8 +/- 3.3 sec, n = 12) with two distinct phases of discharge; the first was characterized, in the dentate gyrus only, by high-frequency, field oscillations (ripples) at 206.3 +/- 23.4 Hz (n = 12), whereas the second component corresponded to afterdischarges in the theta range frequency. Ripples, which were also recorded in "minislices" only of the dentate gyrus, were unaffected by application of the mu-opioid receptor agonist (D-Ala2-N-Me-Phe,Gly-ol)enkephalin (10 microM; n = 6) or the N-methyl-D-aspartate (NMDA) receptor antagonist 3-(2-carboxy-piperazine-4-yl)-propyl-l-phosphonate (10 microM; n = 5). In contrast, the non-NMDA glutamatergic receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM; n = 5) completely blocked all picrotoxin-induced activities. In addition, application of the GABA(B) receptor agonist baclofen (0.01-0.5 microM; n = 6) dose dependently and reversibly abolished all picrotoxin-induced activities. We also found that application of the gap-junction decouplers carbenoxolone (0.2-0.5 mM; n = 6) or octanol (0.2-0.5 mM; n = 3) blocked the second phase while leaving ripples unchanged. These findings demonstrate that the disinhibited dentate gyrus can generate ripple activity at approximately 200 Hz that is contributed by ionotropic glutamatergic mechanisms and is not dependent on either GABA(A) receptor-mediated or gap-junction mechanisms.
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PMID:Ripple activity in the dentate gyrus of dishinibited hippocampus-entorhinal cortex slices. 1574 60

Glycine receptor channels are pentameric ligand-gated ion channels that respond to the application of inhibitory neurotransmitters by opening of a chloride-selective central pore. Topiramate (TPM) is a broad-spectrum antiepileptic drug used as add-on or monotherapy for focal seizures. In the present study the interaction of TPM with glycine receptor channels was studied on outside-out patches from HEK293 cells expressing alpha1beta glycine receptor channels. The patch clamp techniques combined with ultra fast solution exchange enabled us to investigate the kinetics of receptor channels in presence of TPM. Our study showed no agonistic or potentiating effect for TPM on glycine receptor channels. However, in presence of 1 mM glycine + 1 mM TPM, the desensitization got faster and the peak current amplitude decreased. After the end of glycine + TPM pulses, off-currents occurred, suggestive for a specific channel block mechanism.
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PMID:Interaction of topiramate with glycine receptor channels. 1582 41

Glycine encephalopathy (GE) (non-ketotic hyperglycinemia) is an autosomal recessive neurometabolic disease caused by defective activity of the glycine cleavage system. Clinically, patients present usually in the neonatal period with hypotonia, encephalopathy, hiccups and breath arrests with or without overt seizures. GE is considered rare, but its incidence is relatively high in several geographical areas around the world. We report a novel mutation causing GE in six extended Arab families, all from a small suburban village (population 5,000). A methionine to threonine change in the initiation codon of the glycine decarboxylase gene led to markedly reduced glycine decarboxylase mRNA levels and abolished glycine cleavage system activity.
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PMID:A single nucleotide substitution that abolishes the initiator methionine codon of the GLDC gene is prevalent among patients with glycine encephalopathy in Jerusalem. 1586 13

Glycine encephalopathy is a rare autosomal recessive metabolic disease characterized by glycine accumulation in body fluids owing to a defect in the glycine cleavage system. There are several forms of glycine encephalopathy. In the classic or neonatal form, symptoms usually develop as neurologic symptoms in the first few days of life. It characteristically presents with hypotonia, lethargy, apnea, and seizures and usually results in death by 1 year of age. In this report, we present two cases of neonatal glycine encephalopathy accompanied by isolated pes equinovarus deformity.
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PMID:Two cases of glycine encephalopathy accompanied by pes equinovarus. 1599 6

Inherited disorders of neurotransmitters are a group of neurometabolic syndromes attributable to a primary disturbance of neurotransmitter metabolism or transport. This is an enlarging group of recognized disorders requiring specialized diagnostic procedures for detection. This review considers clinical disorders of biopterin, catecholamines, serotonin, glycine, pyridoxine, and GABA metabolism. Newly described syndromes such as cerebral folate deficiency and pyridoxal-5-phosphate dependency are included. The disorders of the metabolic pathways of biopterin, catecholamines, and serotonin are linked due to their common synthetic components. Glycine encephalopathy represents an enlarging phenotype related to abnormalities of the glycine degradative cleavage system. Both pyridoxine and pyridoxal-5-phosphate dependency need to be considered in refractory neonatal seizures. The most common disorder of GABA metabolism is SSADH deficiency, which has a broad phenotype of mental retardation, epilepsy, ataxia, and hyporeflexia and which invokes the combined problems of elevated brain GABA and GHB.
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PMID:Inherited disorders of neurotransmitters in children and adults. 1629 54


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